Biapenem BIPM Lot No g mg

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1 MexAB-OprM BIPM imipenemcilastatinipmcs MEPM 3 MexAB-OprM BIPM IPMCS MEPM MexAB-OprM MexCD-OprJ BIPM MEPM IPMCS BIPM IPMCS MEPM 10 5 order CFUlung BIPMIPM CS MEPM 10 6 order CFUlung BIPM IPMCS MEPM Key words: Pseudomonas aeruginosamexab-oprmpneumonia infection model BiapenemBIPM 1 BIPM ceftazidime,3 BIPM dehydropeptidase-i 4 MEPM MexAB-OprM 57 MexAB-OprM MexAB-OprM BIPM in vivo MexAB-OprM BIPM in vitro in vivo imipenemcilastatinipmcs MEPM BIPM I 1 BiapenemBIPMLot No g mg ImipenemcilastatinIPMCSLot No. 6BA95P445 mg MEPMLot No. ST mg TH-4665 TH-768MexAB-OprM TH-5157MexAB-OprM MexCD-OprJ 3 MexBOprM OprJ Gotoh 8 MexB OprM OprJ Western- Blot Table 1 TH-4665 BIPMIPMCS MEPM MIC gml TH-768 TH-5157 BIPMIPMCSMEPM MIC 4 8gmL 43 gml 7

2 Table 1.Expression of MexB, OprM, and OprJ in strains Strain Antibiotics MIC g/ml MexB OprM OprJ TH TH TH MexB: Ratio when signal from PAO-15 gis 1 OprM: Ratio when signal from PAO-15 gis 1 OprJ: Not induction 3 4 ICR cyclophosphamidesigma 00 mgkg 4 Mueller-Hinton agarmhadifco MHA A6 nm optical densityo. D 0.03 O. D 0.3 Pentobarbital sodium somnopentyl Schering- Plough Animal Health 0L 5 AUC AUC 4,911 AUC BIPMIPMCS MEPM 1 mgkg ml 10 MHA L 37 CFUlung 7 SAS Steel Steel-Dwass II 1MexAB-OprM TH-4665 BIPM IPMCS MEPM Table 4 log CFUlungS.D BIPM mgkg IPMCS mgkg MEPM mgkg.53 log Table MexAB-OprMTH-768 MexAB- OprM MexCD-OprJ TH-5157 BIPMIPMCS MEPM Table TH BIPM IPM CS MEPM 5.5 log Table BIPM TH-768 IPMCS MEPM P0.05TH BIPM IPMCS MEPM 4.5 log Table BIPM TH-5157 IPMCS MEPM P0.05 TH order 10 6 order CFUlung BIPM IPM CS MEPM Fig order CFU lung 4

3 Table.Therapeutic efficacies of, imipenem/cilastain and in a mouse model of infection pneumonia with Pseudomonas aeruginosa Strain P. aeruginosa TH-4665 carbapenem-sensitive strain P. aeruginosa TH-768 MexAB-OprM over-producing strain P. aeruginosa TH-5157 MexAB-OprM over-producing and MexCD-OprJ producing strain Inoculum size Log CFU/lung Antibiotics Dose mg/kg 1: P<0.05vs : P<0.05vs imipenem/cilastain, and 3: P<0.05vs and 4: P<0.05vs and : Vaible cells of lung of hours after infectionujst first administration with antibiotics, mean: n=5 Vaible cell of lung Log of CFU/lung±S.D.± ± ± ±0..90± ± ± ± ± ± ± ±0.50 Fig. 1. Influence of inoculum size on therapeutic efficacy of BIPM, imipenemcilastatinipm CS, and MEPMagainst carbapenem-sensetive Pseudomonas aeruginosa TH-4665 in a mouse pneumonia model. AInoculum sizelog CFUlung:5.83Two hours after infection P0.05vs BInoculum sizelog CFUlung:6.84Two hours after infection P0.05vs IPMCS, MEPM,, P0.05vs BIPM IPMCS MEPM 34logBIPM IPMCS MEPM Fig. 1A10 6 order CFUlung BIPM IPMCS MEPM 1 log BIPM IPMCS MEPM P0.05Fig. 1B III MexAB-OprM 5,6 MexAB-OprM MEPM MexAB-OprM MEPM 1 BIPM IPM 13 in vivo MexAB-OprM BIPMIPMCS MEPM

4 BIPMIPMCS MEPM MexAB-OprM BIPM IPMCS MEPM MexAB- OprM MexCD-OprJ BIPM MEPM IPMCS MexAB-OprM MIC MexAB- OprM MEPM MEPM 1 in vivo β 14,15 BIPM IPMCS MEPM 10 5 order CFUlung BIPM IPMCS MEPM 10 6 order CFUlung BIPM IPMCS MEPM P 0.05BIPM IPMCS MEPM 16 BIPMIPMCS MEPM in vitro BIPM IPMCS MEPM 14 BIPM MEPM IPMCS MEPM BIPM BIPM in vitro BIPM MexAB-OprM IPMCS MEPM IPMCS MEPM BIPM 1 Chemotherapy 4S-4:119, Jpn J Antibiot 54: , Biapenem Jpn J Antibiot 55: 6776, 00 4 Biapenem Chemotherapy 4S- 4: 4350, Pseudomonas aeruginosa 47: , Masuda N, Sakagawa E, Ohya S, et al: Substrate specificies of MexAB-OprM, MexCD-OprJ, and MexXY- OprM efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother 44: 33337, Wong K K Y, Poole K, Hancock R E: Influence of OprM expression on multiple antibiotic resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 41: 00901, Gotoh N, Tsujimoto H, Tsuda M, et al: Characterization of the MexC-MexD-OprJ multidrug efflux system in mexa-mexb-oprm mutants of Pseudomonas aeruginosa. Antimicrob Agents Chemother 4: , Biapenem Chemotherapy 4S-4: 7784, Meropenem Chemotherapy 40S- 1: 13131, Meropenem I Chemotherapy 40S-1: 5875, Masuda N, Ohya S: Cross-resistance to, cephems, and quinolones in Pseudomonas aeruginosa. Antimicrob Agents Chemother 36: , Shibata K, Adachi Y, Kato E, et al: In vitro and in vivo evaluation of BO-77 against imipenem-and or -resistant Pseudomonas aeruginosa. J Antibiot 50: , Biapenem in vitro Chemotherapy 4S-4:91101, Panipenembetamipron in vitro in vivo Chemotherapy 39S-3:5574, in vitro 51: , 003

5 In vivo efficacy of against mouse pneumonia infection caused by MexAB-OprM overproducing Pseudomonas aeruginosa Toshihiko Takata 1, Atsuyuki Shimizu 1, Muneo Hikida 1, Naomasa Gotoh and Takeshi Nishino 1 Infectious Disease Reseach Laboratories, Meiji Seika Kaisha, Ltd., 7 Morooka-cho, Kohoku-ku, Yokohama, Kanagawa, Japan Department of Microbiology, Kyoto Pharmaceutical University In vivo efficacy of BIPMagainst mouse pseudomonal pneumonia infection was compared to that of imipenemcilastatinipmcsand MEPM. All carbapenems showed high therapeutic efficacy against sensitive P. aeruginosa. BIPM efficacy against the MexAB-OprM overproducing strain was superior to IPMCS and MEPM. Therapeutic response of BIPM against MexAB-OprM overproducing and MexCD-OprJ producing strain was superior to MEPM and similar to IPMCS. BIPM effectiveness was compared to IPMCS and MEPM using a mouse model infection with different inoculum size. In 10 5 order CFUlung, therapeutic efficacy of BIPM, IPMCS, and MEPM was comparable, but in 10 6 order CFUlung, BIPM showed higher efficacy than IPMCS or MEPM.